The renal handling of amylase in normal man.

The renal glomerular and tubular transport rate of amylase was studied by measuring the urinary excretion of this protein before and during inhibition of tubular protein reabsorption by lysine. The excretion of amylase was compared with the excretion of albumin, beta-2 microglobulin and free light chains of immunoglobulins. This investigation showed that amylase is reabsorbed by the tubular cells, but only to a very modest degree compared with the reabsorption of the other three proteins. In the case of amylase only about 45% of the filtered molecules are reabsorbed, whereas more than 90% of the filtered amount of the other molecules is reabsorbed by the tubular cells. The excretion of amylase rose after lysine injection only by a factor 1.8, whereas excretion rose by a factor 28 for albumin, 1,500 for beta-2 microglobulin, 16 for kappa chains and 8 for lambda chains. Minimal values for tubular reabsorption were found to be 5.5 +/- (SD) 4.3 U/min for amylase, 174.0 +/- 35.7 micrograms/min for albumin, 90.5 +/- 14.4 micrograms/min for beta-2-microglobulin, 70.4 +/- 17.4 micrograms/min for kappa chains and 24.2 +/- 9.2 micrograms/min for lambda chains.     

Silicon metabolism. II. Renal handling in chronic renal failure patients

In 36 patients suffering from chronic renal failure (mean creatinine clearance 26 ml/min), serum silicon levels were significantly increased (mean 0.52 microgram/ml compared with 0.265 microgram/ml in normals; p less than 0.005). Urinary silicon excretion per 24 h was significantly decreased (15.71 mg/24 h compared with 21.4 mg/24 h in normals; p less than 0.001). Fractional excretion of silicon (FESi) was significantly increased in chronic renal failure (p less than 0.001), with overall tubular secretion of silicon in 33% of patients. Urinary excretion of silicon was significantly related to urinary calcium excretion (p less than 0.0001) urinary magnesium excretion (p less than 0.0001) creatinine clearance (p less than 0.05) and sodium excretion (p less than 0.05). It is suggested that urinary silicon is in the form of orthosilicate, principally bound to calcium and magnesium; and that in chronic renal failure the increase in FESi, and the decrease in absorbed Si from the gastrointestinal tract, moderate the increase in plasma silicon levels and prevent excessive entry of silicon into the tissues.     

Does lithium affect renal sodium handling and renal haemodynamics in normal man?

Renal haemodynamics, sodium excretion, and free-water clearance were evaluated at baseline and after acute frusemide administration in nine moderately volume-expanded healthy volunteers receiving a single administration of either 750 mg lithium carbonate or placebo. Lithium plasma concentration under 0.29 mmol/l exerted no significant effect on renal haemodynamics, on absolute, fractional, or cumulative sodium excretion, or on free-water and chloride clearances at baseline or after frusemide administration. Despite previous volume expansion and presumably depressed proximal reabsorption, frusemide decreased the fractional reabsorption of lithium significantly, suggesting that a small but significant part of lithium may be reabsorbed in the thick ascending limb of Henle's loop. By contrast, frusemide did not change renal haemodynamics or plasma renin activity. Using combined free-water and lithium clearances at baseline and after frusemide administration, fractional reabsorption of sodium in the (FRTAL) was calculated as delta CH2O/CLi, where delta CH2O, the difference in free water clearance before minus after frusemide, is taken as an index of sodium reabsorption in the thick ascending limb, and lithium clearance as an estimation of sodium delivery to the thick ascending limb. FRTAL was calculated in these volume-expanded subjects to lie from 11% to 20% depending on whether some lithium is assumed to be in the thick ascending limb.     

Phenylalanine metabolism in uremic and normal man.

The metabolism of phenylalanine and tyrosine was evaluated in six normal men, five chronically uremic men, and three men undergoing maintenance hemodialysis. Phenylalanine, tyrosine, and 13 acidic metabolites of those amino acids were measured in plasma postabsorptively and in plasma and urine after a phenylalanine load of 100 mg/kg. In addition, five normal subjects and five dialysis patients ingested L-[14C]-phenylalanine (uniformly labeled) with the load. In uremic and dialysis patients, plasma phenylalanine rose higher and fell more gradually after the load, and tyrosine rose more slowly. The 24-hr urinary concentrations of phenylalanine and tyrosine were similar in the three groups. At 24 hr, cumulative expiration of 14CO2 was 20.2% in the dialysis patients and 28.4% in the normal subjects. Plasma phenylalanine levels and 14CO2 expiration varied with protein intake in normal subjects. In uremic and dialysis patients, plasma phenyllactic acid, p-hydroxyphenylacetic acid, and p-hydroxybenzoic acid were elevated, the last one markedly so. Moreover, plasma phenylpyruvic acid (PPA) and mandelic acid were detected only in dialysis patients. After the phenylalanine load, plasma conjugated phenylacetic acid rose in uremic patients, and PPA increased transiently in some dialysis patients. In urine of dialysis patients, concentrations of benzoic acid and conjugated o-hydroxyphenylacetic acid were decreased, and PPA was sometimes increased. The data suggest a mild impairment in the hydroxylation of phenylalanine which does not result in marked changes in plasma or in urinary metabolites after a phenylalanine load.     

Renal handling of silicon in normals and patients with renal insufficiency.

We have compared the renal handling of silicon in 16 patients with renal insufficiency to 14 normal individuals. Silicon, phosphate and creatinine were measured in plasma and urine samples. The renal insufficiency group showed significant increases in plasma silicon (1.28 +/- 0.19 vs. 0.17 +/- 0.03 mg/liter), creatinine (5.19 +/- 0.85 vs. 0.89 +/- 0.03 mg/dl) and phosphate (1.33 +2- 0.11 vs. 1.07 +/- 0.4 mmol/liter). Fractional phosphate excretion was increased in the renal insufficiency group (0.55 +/- 0.07 vs. 0.14 +/- 0.01). In contrast, the fractional excretion of ultrafiltrable silicon was not significantly different between groups (0.78 +/- 0.07 vs. 0.87 +/- 0.06). It is concluded that renal insufficiency does not alter the tubular handling of silicon and that regulatory control of silicon excretion is unlikely.     

The effects of glucagon on protein metabolism in normal man.

Plasma glucagon rises after major injury and could act to increase gluconeogenesis and ureagenesis in the post-traumatic state. This study documents the effect of prolonged glucagon infusion on ureagenesis and nitrogen excretion, as well as possible sources of the increased ureagenesis, in normal man. Four healthy men fasted for 6 days during intravenous infusion of glucose (750 gmday), establishing a steady state of minimal ureagenesis. Glucagon (1 mg/day) then was added to the infusion for 5 days. Glucose alone was given for the final 2 days. Forearm muscle flux of metabolites was determined by standard arterial-deep venous sampling and capacitance plethysmography. Glucagon concentration was suppressed during glucose infusion (11 +/- 13 pg/ml) and rose to levels seen in subjects with major trauma during glucagon infusion (669 +/- 138 pg/ml). Glucose infusion stabilized urine nitrogen excretion at 1.54 +/- 0.42 gm of N/sq m/day. Nitrogen excretion increased to 2.40 +/- 0.53 gm of N/sq m/day with glucagon infusion, with urea accounting for the increased excretion. Excretion of 3-methylhistidine was unchanged. Plasma amino acid concentration was strikingly reduced on the first day of glucagon infusion, where it stabilized. Forearm flux showed a slight net release of amino acid nitrogen during glucose infusion. Addition of glucagon to the glucose infusion resulted in a net uptake of nitrogen by forearm skeletal muscle. These evidences strong suggest that glucagon infusion in normal man increases ureagenesis, not only at the expense of the free amino acid pool, but by the hydrolysis of visceral protein as well, with muscle protein being maintained.     

Effects of dobutamine on renal function in normal man

The effects of graded doses of dobutamine on renal function were studied in eight male volunteers. The infusion rates were 2.5, 5 and 10 micrograms/kg/min. Systolic blood pressure increased by 19% (P less than 0.01), 31% (P less than 0.01), and 44% (P less than 0.01), respectively, while diastolic blood pressure decreased by 17% (P less than 0.02), 17% (P less than 0.02) and 25% (P less than 0.01), respectively. Heart rate increased at the highest dosage by 32% (P less than 0.01). Glomerular filtration rate (GFR) diminished at all three infusion speeds by 10% (P less than 0.02), 9% (P less than 0.05) and 14% (P less than 0.02), respectively, while renal blood flow (RBF) was unchanged. Urine flow rate (UF) decreased by 36% (P less than 0.05) and fractional free water clearance (CH2O/CIn) diminished by 37% (P less than 0.05) at the rate of 10 micrograms/kg/min. Fractional potassium excretion (CK/CIn) decreased by 34% (P less than 0.01) and 44% (P less than 0.01) at the two highest rates. Fractional sodium excretion (CNa/CIn) and fractional chloride excretion (CCl/CIn) were unchanged. Catecholamine levels were unaltered. Plasma renin activity (PRA) rose significantly (P less than 0.05) at the highest infusion rate of dobutamine. It is concluded that dobutamine influences GFR, the clinical significance of which, however, is difficult to evaluate.     

Molecular aspects of renal tubular handling and regulation of inorganic sulfate

The renal proximal tubular reabsorption of sulfate plays an important role in the maintenance of sulfate homeostasis. Two different renal sulfate transport systems have been identified and characterized at the molecular level in the past few years: NaSi-1 and Sat-1. NaSi-1 belongs to a Na(+)-coupled transporter family comprising the Na(+)-dicarboxylate transporters and the recently characterized SUT1 sulfate transporter. NaSi-1 is a Na(+)-sulfate cotransporter located exclusively in the brush border membrane of renal proximal tubular and ileal cells. Recently, NaSi-1 was shown to be regulated at the protein and mRNA level by a number of factors, such as vitamin D, dietary sulfate, glucocorticoids and thyroid hormones, which are known to modulate sulfate reabsorption in vivo. The second member of renal sulfate transporters, denoted Sat-1, belongs to a family of Na+-independent sulfate transporter family comprising the DTDST, DRA and PDS genes. Sat-1 is a sulfate/bicarbonate-oxalate exchanger located at the basolateral membrane of proximal tubular epithelial cells and canalicular surface of hepatic cells. Contrary to NaSi-1, no physiological factor has been found to date to regulate Sat-1 gene expression. Both NaSi-1 and Sat-1 transporter activities are implicated in pathophysiological states such as heavy metal intoxication and chronic renal failure. This review focuses on recent developments in the molecular characterization of NaSi-1 and Sat-1 and the mechanisms involved in their regulation.     

Arginine-stimulated acute phase of insulin and glucagon secretion. I. in normal man.

To document and characterize the immediate phase of glucogen secretion as detected in peripheral blood in man, we have given pulses of L-arginine (0.1 gm. to 10.0 gm.) intravenously over twenty to thirty seconds to twenty-three healthy young men. Peak glucagon and insulin levels averaging four and five times basal levels respectively were reached two to five minutes after arginine administration and had returned to baseline levels by fifteen to thirty minutes. Computing the area above basal for the initial ten minutes after arginine stimulation established a dose-response relationship for the acute phases of glucagon and insulin secretion. A maximal glucagon response was elicited by doses of arginine of 5.0 gm. or greater, whereas for insulin, the plateau was reached at 2.5 gm. of arginine. Sequential 5.0-gm. pulses of arginine administered every thirty minutes showed that there was no augmentation or attenuation of the timing, magnitude (area 0-10 minutes) or absolute peak values reached for either the glucogon or insulin responses. The effect of induced hyperglycemia on the acute phase of insulin and glucagon secretion was assessed by administering the arginine during marked elevation of ambient glucose concentration achieved by the intravenous administration of glucose. This resulted in marked suppression of the acute glucagon response and dramatic accentuation of the insulin response.     

The renal metabolism of pepsinogen A and C in man

Pepsinogen A (PGA) and pepsinogen C (PGC) are almost identical low molecular weight proteins with marked differences in renal handling. PGA is present in large amounts while PGC is almost absent in the urine of healthy subjects. Whether the amount of PGA in the urine represents the total amount of PGA that is extracted, is unknown. We, therefore, assessed the renal metabolism of PGA and PGC by measuring PGA, PGC and creatinine concentrations in the aorta and the right renal vein, and in the urine from patients undergoing elective heart catheterization. The renal extractions of PGA and PGC were not significantly different from the extraction of creatinine: 22%, 18% and 24%, respectively. Sixty-eight percent of PGA and 98% of PGC extracted from the circulation were metabolized by the kidney, and fractional metabolism was closely related to the fractional reabsorption of PGA and PGC from the glomerular filtrate. It is concluded that the kidney metabolizes PGA and PGC. The fractional metabolism of PGA and PGC can be calculated from the fractional reabsorption. Further studies on the renal handling of pepsinogens are warranted as they may provide information on factors affecting renal metabolism of low molecular weight proteins.     

Acute renal failure in man: new aspects concerning pathogenesis. A morphometric study

The morphometric investigation of the proximal and distal tubules, the cortical interstitium, the intertubular capillaries, the renal corpuscles and the juxtaglomerular apparatuses (JGAs) in 56 cases in the oligoanuric, polyuric, and normuric phases of human acute renal failure (ARF), 6 cases of myeloma kidney with clinically confirmed ARF and 21 control kidneys revealed the following: (1) The main pathological change in human ARF is swelling of the epithelial cells of the proximal and distal tubules. Necrosis of these cells was observed in some cases but usually only as single cell necroses. (2) The interstitium of the cortex and of the outer stripe of the outer medulla is significantly widened in most cases of ARF. (3) In proximal tubules proximal to occluding casts (which were observed only in the plasmacytoma cases), the lumina are not widened but are narrower than normal, and the cross-sectional area of the epithelium is not greater but smaller than normal. (4) The JGAs were significantly larger in kidneys in the oligoanuric phase of ARF (with 1 exception) than in normal kidneys. In the normuric and polyuric phases they were slightly (not significantly) smaller than normal. In myeloma kidneys with occluding casts and/or diffuse interstitial fibrosis, the JGAs were significantly smaller than normal. From these findings it is concluded that: (1) The fall in glomerular filtration rate (GFR) in the postshock phase of ARF is not caused by nonselective back-diffusion of the primary urine through necrotic tubules or by compression of the lumina of the proximal and distal tubules by interstitial edema. A fall in GFR associated with occluding casts in the distal tubules is found only in the myeloma kidney and does not lead to widening of the proximal tubules but to tubular atrophy and narrowing of the lumen. (2) The casts seen in the lumina of the ascending limb of Henle's loop in some cases of ARF, which consist of hemoglobin, Tamm-Horsfall protein or desquamated blebs, do not occlude the lumen, since they are not associated with atrophy or luminal dilatation of the proximal tubules. (3) The JGAs with their secretory product renin-angiotensin II, together with adenosine, which is released in kidneys with ischemic or toxic damage, play a critical role in the pathogenesis of ARF. (4) In myeloma kidneys with ARF, in which the JGAs are markedly atrophic, the potentiated effect of adenosine that has been observed with a chronic absence of urine flow probably leads to a progressive, irreversible drop in GFR associated with tubular atrophy.